Myocardial infarction is one of ischemic heart diseases. It is a disorder that causes myocardial necrosis where constriction of cardiac coronary artery occurs due to arteriosclerosis and such, and the bloodstream of the coronary artery becomes dramatically reduced or stopped. The expansion and/or deterioration of infarcted area cause complications such as heart failure and/or ischemia-induced severe arrhythmia, and increase threat to life.
As myocardial infarction progresses, myocardial cells in infarcted areas die and/or slough off, and are displaced with fibrous tissues such as collagen fiber. Such infarcted area lacks contractility, and fails to withstand the intracardiac pressure that rises with cardiac contraction, and then the fibrous wall extends thinly. As a result, to compensate for the hypofunction, hypertrophy of the endocardial cavity in non-infarcted area and dilatation of the whole left ventricle are induced. This phenomenon is called left ventricular remodeling and is known to further decrease the cardiac function and increase the morbidity and mortality thereafter. Therefore, for improving prognosis of myocardial infarction, it is considered important to suppress the progression of left ventricular remodeling as early as possible, and development of effective treatment methods is desired.
IL-6 is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-cell lymphocytes (Non-Patent Document 1), and was later revealed to be a multifunctional cytokine that influences the function of various cells (Non-Patent Document 2). IL-6 has been reported to induce maturation of T lymphocyte cells (Non-Patent Document 3).
IL-6 transmits its biological activity via two kinds of proteins on the cell. One of the proteins is the IL-6 receptor which is a ligand binding protein to which IL-6 binds and has a molecular weight of about 80 kDa (Non-Patent Documents 4 and 5). In addition to a membrane-bound form that penetrates and is expressed on the cell membrane, the IL-6 receptor is present as a soluble IL-6 receptor which mainly consists of the extracellular region of the membrane-bound form.
The other is the membrane protein gp130 which has a molecular weight of about 130 kDa and is involved in non-ligand binding signal transduction. The biological activity of IL-6 is transmitted into the cell through formation of the IL-6/IL-6 receptor complex by IL-6 and IL-6 receptor and binding of the complex with gp130 thereafter (Non-Patent Document 6).
IL-6 inhibitors are substances that inhibit the transmission of IL-6 biological activity. Until now, antibodies against IL-6 (anti-IL-6 antibodies), antibodies against IL-6 receptors (anti-IL-6 receptor antibodies), antibodies against gp130 (anti-gp130 antibodies), IL-6 variants, partial peptides of IL-6 or IL-6 receptors, and such are known.
There are several reports regarding the anti-IL-6 receptor antibodies (Non-Patent Documents 7 and 8; and Patent Documents 1-3). A humanized PM-1 antibody, which had been obtained by transplanting into a human antibody, the complementarity determining region (CDR) of mouse antibody PM-1 (Non-Patent Document 9), which is one of anti-IL-6 receptor antibodies, is known (Patent Document 4).
Until now, it has been suggested that IL-6 affects the function and structure of the heart in view of the facts that it negatively influences the myocontractility (Non-Patent Document 10), that cardiac hypertrophy develops in mice in which gp130 is constantly activated due to overexpression of IL-6 and IL-6 receptors (Non-Patent Document 11), and so on. After myocardial infarction, IL-6 is expressed in the left ventricle, in particular, in the border zone of reperfused myocardial infarction (Non-Patent Document 12), and the expression level is related to the size of the left ventricular (LV) after myocardial infarction (Non-Patent Document 13). Furthermore, it has been reported that myocardial cells generate IL-6 under low oxygen stress (Non-Patent Document 14), and that cytokine expression in non-muscular cells during the post-infarction remodeling plays a regulating role in the changes of extracellular matrix (Non-Patent Document 15). Moreover, regarding the relation between myocardial infarction and IL-6, the JAK/STAT system activated via IL-6 is reported to act protectively on myocardial infarction (Non-Patent Document 16).
On the other hand, according to an experiment using IL-6 knockout mice, it is reported that IL-6 deficiency had no influence on the size of infarcted area, left ventricular remodeling, or such (Non-Patent Document 17). As described above, the role of IL-6 in myocardial infarction and left ventricular remodeling after myocardial infarction was unknown.
Prior art references related to the present invention are shown below.
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[Non-Patent Document 2] Akira, S. et al., Adv, in Immunology (1993) 54, 1-78
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[Non-Patent Document 10] Finkel, M. S. et al., Science (1992) 257, 387-389
[Non-Patent Document 11] Hirota, H. et al., Proc. Natl. Acad. Sci. USA (1995) 92, 4862-4866
[Non-Patent Document 12] Gwechenberger, M. et al., Circulation (1999) 99, 546-551
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[Patent Document 1] WO 95/09873
[Patent Document 2] French Patent Application Publication No. FR 2694767
[Patent Document 3] U.S. Pat. No. 5,216,128
[Patent Document 4] WO 92/19759